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MC sources for complex beamsTwo new Monte Carlo sources enable accurate simulations of advanced radiotherapy.Advanced radiotherapy modalities, such as volumetric-modulated arc therapy (VMAT), RapidArc, tomo-therapy and CyberKnife radiosur-gery, employ sophisticated dose calculation engines for treatment planning. As such, Monte Carlo sim-ulations could prove invaluable for patient-specific treatment plan qual-ity assurance (QA) of these complex beam delivery techniques.

In order to realistically represent the beam delivery and dose depo-sition, however, such simulations require the ability to model continu-ously variable beam configurations and complex treatment geometry and kinematics. To this end, Julio Lobo and Tony Popescu have devel-oped two new sources for the widely used DOSXYZnrc Monte Carlo code.

Lobo, from the University of Brit-ish Columbia (Vancouver, BC), and Popescu, from the British Colum-bia Cancer Agency in Vancouver, Canada, have employed the sources to simulate radiotherapy techniques previously regarded as too complex for routine Monte Carlo simulations (Phys. Med. Biol. 55 4431).

“I was more than aware of the challenges faced by those who per-formed Monte Carlo simulations of intensity-modulated arc therapy,” Popescu explained. “For the last dec-ade, the paradigm was to perform brute-force simulations, involving the reading, writing, storage and transfer of hundreds of large ‘phase space’ and dose files, which render such simulations computationally prohibitive. My goal was to move towards quasi-continuous simula-tions, free of resolution limitations, and completely eliminate intermedi-ate phase spaces.”

Extensive approachThe sources – referred to as Sources 20 and 21 – support a continuously moving gantry, collimator rotation, variable monitor unit rate, couch rotation and translation, arbitrary isocentre motion and variable source-to-axis distance, as well as dynamic multileaf collimator (MLC) motion and dynamic jaw motion. These features make them suitable for simulating the above-mentioned radiotherapy techniques.

Source 20 uses a phase space input, while Source 21 uses a full BEAMnrc simulation as the input. According to the authors, one unique feature of these sources is the synchroniza-tion between the motion of the linac components (modelled in BEAM-nrc) and the motion in the machine-

patient geometry (modelled in DOSXYZnrc).

“With rotational/helical IMRT, we have to deal with an intricate inter-play between the continuous motion within the machine head and the motion of the machine around the patient,” explained Popescu. In a clinical treatment plan, the position of each MLC leaf is precisely corre-lated with the gantry position at any given time. A Monte Carlo simula-tion, however, is a statistical sam-pling experiment with no associated natural timescale. Thus synchroni-zation is achieved by time-stamping the particles – taking a particle that passed through a specific MLC aper-ture and sending it into the patient from the gantry angle corresponding to that configuration.

“The only sources that can achieve this are 20 and 21,” Popescu said.

Key comparisonsLobo and Popescu validated the sources via comparison with results from existing source codes under equivalent geometric conditions. For example, they compared a seven-field head-and-neck IMRT plan simulated as a single arc using Source 20 with a field-by-field simulation using Source 2. The Source 20 simulation was achieved in a single run, while Source 2 required seven independent Monte Carlo runs. The two plans showed virtually identical dose distributions and dose-volume histograms.

They note that Source 20 is now

used routinely at the British Colum-bia Cancer Agency in Vancouver for patient-specific RapidArc QA. Dynalog files (containing MLC posi-tions and gantry angles) recorded by the linac during beam delivery act as inputs to the Monte Carlo simu-lations. A typical Source 20 simula-tion takes 4–6 hours to run on 10–20 nodes of the institution’s Monte Carlo cluster, leading to a statistical uncertainty of less than 1% in the high-dose voxels.

Comparisons of Monte Carlo results with ionization chamber measurements in a cylindrical phan-tom show typical differences of less than 1%. The researchers also saw excellent agreement between Source 20 calculations and dose calcula-tions performed by the Eclipse treat-

ment planning system.“In principle, Source 21 would

suffice for all Monte Carlo simula-tions,” said Popescu. But in practice, he noted, routinely simulating the full linac head where not essential may prove computationally costly. Source 20 is ideal for RapidArc and tomotherapy, where the jaw setting is fixed throughout treatment. Other technologies, such as Elekta VMAT or the newly proposed dynamic tomo-therapy, require the use of Source 21.

The researchers are currently devel-oping a QA process for Elekta VMAT, in collaboration with Toronto’s Prin-cess Margaret Hospital. Other poten-tial applications of Sources 20 and 21 include a dual-source (kV and MV) for Varian’s TrueBeam technology that models cone-beam CT acquisi-tion during RapidArc delivery using interlaced beam pulses; or multiple arcs with couch rotation for stere-otactic radiosurgery and lung or liver SBRT with RapidArc.

“My presentation of the new source codes at the Monte Carlo Treatment Planning workshop in Cardiff last year attracted quite a bit of interest and I have already received several requests for the source pack-age,” Popescu told medicalphysicsweb. “They will soon be added to the standard BEAMnrc/DOSXYZnrc distribution, to be available to any user of these codes.”

Tami Freeman is editor of medicalphysicsweb.

“I was more than aware of the challenges faced by those who performed Monte Carlo simulations of intensity-modulated arc therapy.”

Complex motion: Monte Carlo simulations (inset) of the dose distribution from a moving CyberKnife beam.

Accu

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Tony

Pop

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focus�on:�radiation�therapy

VMAT: determining the delivered doseVolumetric-modulated arc therapy (VMAT) exploits continuous varia-tions in gantry angle, dose rate and multileaf collimator (MLC) aperture to deliver a conformal dose distri-bution in a short treatment time. This conformality assumes that the patient position and anatomy remain constant and that the delivery system functions as expected. In reality, this is not necessarily the case.

A research team at Stanford Uni-versity School of Medicine (Stanford, CA) has now developed a procedure for retrospectively reconstructing the actual dose delivered in VMAT, based on pre-treatment cone-beam CT (CBCT) and dynamic log files (Phys. Med. Biol. 55 3597).

“Despite all the efforts in patient-specific quality assurance, up to this point, radiation therapy QA has, at best, been an open-loop process,” explained researcher Jianguo Qian. “Our motivation is to close the loop by providing the radiation oncology community with a technical method to ‘see’ what has actually been deliv-ered to the patient.”

The proposed method involves performing CBCT immediately prior to dose delivery and retrieving the system’s log files (which contain MLC leaf positions, gantry angles and cumulative monitor units) after-wards. These data are used to update the original DICOM-RT file, which is

then imported into the Eclipse treat-ment planning system for calcula-tion of delivered dose.

The researchers evaluated the accuracy of this calculation by recording a planning CT of a phan-tom and creating a single-arc Rapi-dArc plan for three hypothetical targets. They then acquired CBCT images and recalculated the dose distribution by applying the original delivery parameters.

Comparing original and CBCT-based plans revealed good agreement between the two. The dose-volume histogram of the CBCT-based plan

showed a dose increase of 0.8% for the target volume compared with the original plan, while discrepancies in maximum and mean target dose were 1.3% and 0.7%, respectively.

Next, the team generated two RapidArc plans on the phantom’s planning CT; both included a cuboi-dal target and one also contained an organ-at-risk. Following dose deliv-ery, pre-treatment CBCT images and log file parameters were used to calculate dose distribution. Any deviations in machine parameters were recorded in the log-files, while any organ motion/deformation was

reflected in the CBCT. The dose distri-bution thus represents the actual dose received. The researchers also calcu-lated doses for the original plan on the CBCT and the reconstituted plan on the planning CT. Dosimetric differ-ences between the original and three calculated plans were insignificant.

Finally, the team examined the influence of inter-fractional set-up errors using a pelvis phantom with an elliptical target. A single-arc plan was delivered three times: with the phantom positioned as planned, off-set by 2 mm and offset by up to 5 mm.

In the absence of set-up errors, the reconstructed dose showed no sig-nificant difference from the original plan. When moderate errors were introduced, a considerable shift in high-dose levels was observed, while the larger offset caused the high-dose region to deviate significantly.

The dose to the target for the origi-nal and CBCT-based plans agreed to within 1.3% in the error-free case. However, compared with the origi-nal plan, the minimum dose to target was reduced from 94.8% to 76.1 and 47.3%, for moderate and large shifts, respectively. The study highlights the importance of accurate patient set-up for VMAT, with CBCT-based dose reconstruction proving a powerful tool for visualizing the dosimetric consequences of inter-fractional motion.

GPUs speed IMRT replanningOnline adaptation of intensity-mod-ulated radiotherapy (IMRT), in which treatment is replanned according to the daily cone-beam CT scan, prom-ises to significantly reduce normal tissue toxicity and improve target coverage. Ideally, the modified plan should be created immediately prior to delivering each treatment fraction. This does, however, place strict time constraints on the replanning proc-ess, which must be performed within a few minutes while the patient is in the treatment position.

One way to enable real-time replanning is via the use of graph-ics processing units (GPUs). With hundreds of processing cores, GPUs offer high-performance computing that’s affordable for a clinical set-ting. Researchers at the University of California, San Diego (UCSD) have already established the effectiveness of this approach, showing that GPUs can perform three key replanning tasks – anatomy segmentation, dose calculation and plan optimization – in a matter of seconds.

Now, the UCSD team has dem-onstrated an improved method for the plan optimization stage: direct aperture optimization (DAO). IMRT plans are traditionally optimized via a two-stage process involving f lu-ence map optimization followed by multileaf collimator (MLC) leaf

sequencing. This approach has two major drawbacks: a potential loss in treatment quality, and the large number of monitor units (MUs) pro-duced by fluence map optimization. DAO, on the other hand, integrates the two stages into a single model (Phys. Med. Biol. 55 4309).

“DAO considers the hardware lim-itations and tries to minimize total MUs by optimizing the MLC leaf sequences directly and eliminating the leaf sequencing step,” explained Steve Jiang, executive director of the University’s Center for Advanced Radiotherapy Technologies (CART). “DAO produces higher-quality plans since the planned dose distribution is closer to the delivered dose distri-bution and the total MUs are often smaller, thus the treatment time is shorter and the leakage/scatter dose

is smaller.” To solve the DAO problem, the

researchers employed column gen-eration, which iteratively solves a sub-problem and a master problem. In each iteration, an aperture can-didate is added to a given pool of allowed apertures; the master prob-lem is to find the optimal intensities for these selected apertures.

Jiang and co-authors Chunhua Men and Xun Jia, postdoctoral fellows at CART, evaluated this approach by designing treatment plans for five head-and-neck cancer and five pros-tate cancer patients. The prostate cancer cases used nine 6 MV co-pla-nar beams, while the head-and-neck cases employed five beams. A beam-let size of 5 × 5 mm2 and a voxel size of 2.5 × 2.5 × 2.5 mm3 were used for all targets and organs at risk.

Calculations were performed on a Tesla C1060 card from NVIDIA (Santa Clara, CA) and using NVID-IA’s CUDA development platform. The researchers employed a conver-gence stopping rule that halts the calculation when the treatment plan quality has not improved markedly (with respect to a particular target or critical-structure criterion) over five iterations.

High-quality plans were obtained for all patients, with optimization times ranging from 0.7 to 1.8 s for the prostate-cancer cases and from 0.9 to 3.8 s for the head-and-neck cases. The same problems took 2–3 min to solve using a 2.27 GHz Intel Xeon CPU. Analysis revealed minimal dif-ferences between results obtained using the GPU and the CPU. The authors note that DAO-based plan-ning is suitable both for initial treat-ment plan optimization on planning CTs and for plan re-optimization based on daily CBCT images.

“We are currently integrating the GPU replanning tools into a research platform. The tools and platform will be made available to the research community to conduct clinical research,” said Jiang. “We are also trying to collaborate with treatment-planning system vendors to incorporate our GPU tools into clinical planning systems.”

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DAO implementation: treatment plan for a prostate cancer case; (a)dose-volume histograms; (b) dose colour wash/isodose on a CT slice.

Intra-fractional motion can signifi-cantly compromise the benefits of IMRT and devising ways to tackle this problem is a highly active field of research. Dynamic multileaf collima-tor (MLC) tracking of tumour motion is one such promising method.

Researchers at the German Can-cer Research Centre (DKFZ) in Hei-delberg have successfully integrated electromagnetic real-time tumour position monitoring into an MLC-based tracking system – in what they believe is a significant step towards clinical implementation of this par-ticular motion-management tech-nique (Int. J. Radiat. Oncol. Biol. Phys. doi: 10.1016/j.ijrobp.2010.03.043).

The DKFZ team used the position monitoring system from Calypso Medical Technologies (Seattle, WA), which involves three transponders being implanted around the target volume. To address dose delivery, they modified a Siemens 160 MLC to include dynamic tumour tracking control (DTTC) software for adapt-ing the MLC aperture in real time.

“Our DTTC software was devel-oped in close collaboration with Siemens and communicates over a network with the Calypso sys-tem and the MLC control system,” DKFZ scientist Andreas Krauss told medicalphysicsweb. “We receive one central point from Calypso, which combines the position of all three transponders and we use this to opti-mally adapt the leaf positions. The modifications we made to perform the dynamic tracking are not com-mercially available.”

The researchers carried out tests to evaluate the dynamic tracking system’s latency, geometric accu-racy and dosimetric accuracy. The overall system latency was found to be 500 ms, a figure largely dominated by the processing time of the MLC control unit. In terms of geometric accuracy, RMS errors of 0.69 and 0.8 mm were observed for the direc-tions parallel and perpendicular to the leaf travel direction, respectively.

Finally, to investigate the clini-cal benefits of the tracking system, dosimetric accuracy was assessed for a five-beam IMRT plan applied to a phantom. Three scenarios were investigated: radiation delivery in static MLC mode; delivery to a moving target in static MLC mode; and delivery to a moving target in dynamic MLC tracking mode.

“The strong underdosage of the tumour edge travelling out of the treatment field without tracking applied could be compensated effec-tively,” conclude the DKFZ team. “The 2%/2 mm gamma-failure rate decreased from 99.6 to 8.6% . The overdosage of the surrounding tissue travelling into the treatment beam without tracking showed that the dose gradients intended to protect healthy tissue from an excessive dose were severely compromised without tracking.”

DMLC tracking tackles motion

Dose distributions: original plan on the planning CT (a). Reconstituted plans on a phantom with no (b) moderate (c) and large (d) set-up errors.

4 focus on: radiation therapy

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The benefits of radiotherapy for lung cancer are undeniable. Yet these must always be weighed up against the possibility of radiation-induced lung toxicity (RILT) developing after irradiation of lung tissue. Although the risk of radiation damage is known to increase at higher doses, the standard method of predict-ing RILT based solely on dosimet-ric factors is not ideal. Speaking at the recent ESTRO 29 meeting in Barcelona, Spain, Philippe Lambin explained how RILT predictive mod-els could be improved.

Lambin, medical director of the Maastro Clinic in the Netherlands, explained that for radiation treatment of thoracic cancers, the dose-limiting factor is irradiation of normal lung tissue. The ability to predict the like-lihood of lung damage in a particular patient enables better individualiza-tion of their treatment plan.

One option is the implementa-tion of isotoxic treatment. Here, the tumour dose is not fixed, but instead, a preset rate of complications is defined and as high a dose as possible is delivered to comply with this limit. “When we can better predict compli-cations, we can better increase the dose and this translates to a better outcome,” Lambin told delegates.

Ramp the variablesLambin explained that RILT predic-tion based on variables such as mean lung dose (MLD) or V20 (lung vol-ume receiving 20 Gy or more) can act as a baseline reference. But the predictive model can be improved by incorporating other, non-dosimetric parameters.

One option could be the inclusion of genetic data, as the genetic profile of a patient can affect the incidence of pneumonitis (one example is gene polymorphism of TGFβ). The rela-tionship between RILT and MLD is also dependent upon the location of the tumour. For example, studies in mice have shown that lower parts of the lung are particularly sensitive to radiation damage.

Lambin described a study under-taken at Maastro comparing the predictive power of a multivariate

model – which included WHO-performance status, smoking status, lung function (forced expiratory vol-ume), age and MLD – against models based solely on either V20 or MLD. The study (of 407 patients) revealed that in this group, dosimetric param-eters played a less important role than patient characteristics for pre-dicting lung toxicity.

To help other clinical teams gain more insight into the risks and ben-efits of radiotherapy, Lambin and colleagues have created a website (www.predictcancer.org) in which Maastro prediction models calculate the likelihood of radiation-induced dyspnea, treatment-induced dys-phagia and two year overall survival for patients with lung cancer.

The models provide risk probabili-ties for individual patients, based on combinations of inputs that include age, forced expiratory volume, WHO-status, nicotine use and MLD.

PET predictionLambin also discussed the use of functional imaging techniques such as PET for predicting toxic effects of radiotherapy. He cited a study from Maastricht showing that increased uptake of fluorodeoxyglucose (FDG) in the lung prior to treatment corre-lates with the incidence of radiop-neumonitis. This effect may be due to pre-treatment inflammation making pulmonary tissue more susceptible to radiation damage, and highlights the need to avoid high dose to these high-tracer-uptake regions.

Looking ahead, Lambin suggested that the future lies in the use of such multifactorial prediction models. He also pointed out the need to expand RILT prediction studies to encompass intensity-modulated radiotherapy, arc therapy and proton treatment. To minimize the risks of RILT, he advocated the use of isotoxic treatment, with dose prescribed according to risk factors, selective avoidance of susceptible areas of the lung, and investigation into the use of pharmacological intervention.

“There are no radioresistant tumours, only radiosensitive tis-sues,” said Lambin.

RILT: what’s the risk?

Conventional fractionated radio-therapy is planned using the lin-ear-quadratic (LQ) equation to calculate radiation doses. However, the high-dose fractions used in newer techniques such as stereotac-tic radiosurgery, stereotactic body radiotherapy and high-dose-rate brachytherapy cannot be accurately calculated with this traditional model. To address this problem, researchers at Ohio State University (Columbus, OH) have developed a new mathematical equation: gLQ, the generalized form of the LQ equa-tion, which is valid at both low and high doses (Sci. Transl. Med. 2 39ra48).

Irradiation is thought to cause two

types of DNA damage: lethal lesions that result in immediate cell death, and sub-lethal lesions. The LQ equa-tion does not account for the fact that at high radiation doses, there is less sub-lethal and more lethal DNA damage. The resulting error grows as the dose increases, potentially leading to inadequate treatments. The new equation can accurately calculate the amount of sub-lethal damage to cells. Comparisons with published studies – which measured the effects of differ-ent radiation doses on cells grown in vitro and in animals – confirmed that the gLQ model can accurately predict the killing effects of radiation through a wide dose range (up to 13.5 Gy).

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5focus on: radiation therapy

IGRT: introducing the next generationThe quest for optimal tumour tar-geting in radiotherapy inspires the ongoing evolution and emergence of innovative treatment systems. One case in point is Vero, a next-generation stereotactic body radio-therapy (SBRT) system launched at the recent ESTRO 29 meeting in Bar-celona, Spain.

Vero is a joint product from Brain-LAB of Germany, which developed the software, and Mitsubishi Heavy Industries in Japan, which came up with the hardware. The instrument’s key selling point is its combination of versatile imaging capabilities and a unique gimballed accelerator sys-tem – with the potential for real-time tumour tracking – in one advanced integrated treatment system.

Vero comprises a 6 MV linac (the MHI-TM2000) mounted on a ring gantry that rotates around the patient by ±185°. The O-ring can also rotate ±60° about its vertical axis – enabling beam delivery from almost any angle. In addition, the linac-multileaf collimator assembly is mounted on gimbals, allowing pan and tilt motion of the beam. As well as increasing the flexibility of beam delivery, this set-up enables compen-sation for any gantry distortions dur-ing rotation, resulting in an isocentre

accuracy of 0.1 mm. “This gimballed head is the first of its kind in the mar-ket,” said Herbert Frosch, managing director of Vero GmbH. “It ensures that you can treat moving targets with higher precision.”

On the imaging side, Vero boasts a suite of devices: including two orthogonal kilovoltage systems attached to the O-ring for fluoros-copy and orthogonal X-ray imaging; volumetric cone-beam CT; and a megavoltage electronic portal imag-ing device for beam verification. There’s also an integrated ExacTrac infrared marker-based position-ing system that enables real-time patient monitoring. In combination with motion management software, these abilities provide detailed real-time information, to guide patient set-up and positioning, and monitor motion during treatment.

Frosch emphasised that Vero is not being launched as a concept, but as a treatment system that’s ready to be used clinically. In fact, there are now four Vero systems installed in Japan, where some 300 patients have already been treated with Vero SBRT. The first European installation – in UZ Brus-sels University Hospital – started clinical treatment in September.

Speaking at Vero’s official launch

symposium, Timothy Solberg from UT Southwestern Medical Center (Dallas, TX), examined the ongo-ing evolution of radiotherapy tech-niques and the emergence of SBRT. “Technology has really opened avenues for progressive practise of radiation oncology,” he said.

Solberg cited the idea that if one can exploit innovative technologies to deliver higher radiation doses to smaller volumes, one can increase local tumour control – a concept that is being realised with SBRT. The modality first emerged in the early 1990s, and since then has evolved to provide improved accuracy and

reproducibility. Alongside, Solberg explained, the field has seen the emergence of sophisticated treat-ment planning systems, multiple beam delivery, stereoscopic locali-zation, cone-beam CT and more. “All of these technologies have driven the clinical practise of SBRT,” he told ESTRO delegates. “And all are inte-grated into the Vero.”

With a look to the future, Vero’s senior project manager Franz Gum highlighted some ongoing develop-ments of Vero SBRT. One example is dynamic tumour tracking, which is enabled by the system’s novel gimballed linac. The idea is to use

dynamic tumour tracking to treat only the tumour, not the motion envelope. Eliminating the need for beam gating results in an improved duty cycle and reduced healthy tis-sue dose, as well as enabling dose escalation.

To do this, VERO simultaneously acquires the breathing signal of the patient (via infrared tracking) and records a f luoroscopic sequence – enabling correlation of tumour posi-tion with the patient’s breathing. The moving target is then followed using the gimballed linac motion, either with f luoroscopic verification on demand (to minimize patient dose), or with constant tumour tracking via real-time fluoroscopic measure-ments (to maximize precision).

With the hardware already in place and software in the final develop-ment stage, clinical validation of this feature is expected to start next year.

Gum also described a technique dubbed “dynamic wave arc”, in which the gantry and ring structure rotate simultaneously. “You can use this to virtually ‘drive around’ criti-cal structures,” he explained. “It’s a work-in-progress, but we see high potential in this – it adds an addi-tional degree of freedom for treat-ment plan optimization.”

New launch: the Vero SBRT made its European debut at ESTRO 29.

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focus on: particle therapy

Delivering dosimetry in motionScanned ion-beam therapy delivers extremely conformal dose distribu-tions, but as with any precision radi-otherapy modality, intrafractional motion can compromise delivery accuracy. A dedicated phantom that can accurately measure dose distri-bution to a moving target would ena-ble verification of the effectiveness of this technique.

Heavy ions introduce a further complication. The superposition of pencil beams in scanned ion-beam therapy, plus the fragmentation of the primary beam into lighter parti-cles, leads to a mixed irradiation field. The relative biological effectiveness (RBE) varies according to the particle and energy spectrum of this mixed field – resulting in a spatially modu-lated RBE that’s dependent upon the distribution of absorbed dose.

In clinical practice, biological models are used to calculate RBE values. The models themselves can be verified via cell survival experi-ments. Existing biological dosimetry phantoms, however, only measure cell survival distributions in one- or two-dimensions and have not been tested in motion.

Now, researchers at the GSI Helm-holtz Centre for Heavy Ion Research in Darmstadt, Germany, have devel-oped a dynamic biological phan-tom that can effectively measure three-dimensional cell survival dis-tributions and the corresponding distribution of RBE-weighted dose in the presence of motion (Phys. Med.

Biol. 55 2997).The phantom comprised two

MicroWell plates, each containing 96 wells holding Chinese hamster ovary cells. The lateral resolution (well spacing) was 9 mm, while depth resolution was provided by spacing the plates 9 mm apart.

The GSI team investigated the inf luence of motion on the phan-tom’s basic biological properties by conducting measurements with-out irradiation. Cell survival curves following photon irradiation were similar for the stationary and mov-ing phantom. To determine the phantom’s suitability for biological dosimetry of moving targets, the researchers irradiated a target to a dose of 6 Gy (RBE). The treatment plan comprised a regular grid of raster points.

They applied carbon-ion-beam irradiation to the phantom whilst stationary and while undergoing regular sinusoidal motion. Motion was mitigated by real-time adapta-tion of the carbon-ion pencil beams during beam scanning using the GSI beam-tracking system. Dosimetry films verified the beam-tracking per-formance as successful.

Fol low i ng i r r ad iat ion, t he researchers determined the cell sur-vival at various positions within the target. Mean differences between the measured and calculated cell sur-vival were within ±5% of the target dose for both irradiation schemes.

Cell survival after lateral beam tracking was comparable to the sta-tionary reference, especially in the target area, where mean differences were within ±5% . The researchers

converted the cell survival data to RBE-weighted dose and correspond-ing errors. The mean dose errors for the stationary and moving set-ups were 522 and 552 mGy (RBE), respectively. Normalized to the tar-get dose, this corresponds to dosi-metric precisions of 8.7 and 9.2%, respectively, which compares well to reported measurement errors for other phantoms.

Finally, the researchers calculated the dose differences between irradia-tion of the stationary phantom and the beam-tracked phantom at each measurement position. The stand-ard deviation of the mean dose differ-ence between the two was 756 mGy (RBE) or 12.6%, comparable to the calculated total experimental error of 12.7%.

The GSI team concluded that the dynamic phantom is capable of measuring 3D survival distributions for moving targets, with cell survival distributions showing good agree-ment between beam-tracked and static reference irradiation.

“The phantom can be utilized for verification of dose algorithms and for verification of biological mod-els,” noted lead author Alexander Gemmel, also with Siemens Health-care of Erlangen, Germany. “GSI is further developing phantoms for cell survival measurements with controlled oxygenation conditions. Additionally, phantoms with even higher spatial resolution are under investigation.”

The excellent target conformality offered by proton therapy is a con-sequence of the majority of high-energy protons stopping in the target volume and not continuing into nor-mal tissue. However, this does mean that small errors in particle range can have a massive clinical impact.

To date, the most successful method employed to gauge the sever-ity of proton-beam range errors has been PET. But having noted a striking pattern in the bone marrow in post-treatment MR images, researchers at Massachusetts General Hospital (Boston, MA) and Vanderbilt Uni-versity School of Medicine (Nash-ville, TN) believe that this imaging modality offers an opportunity to visualize radiation effects in vivo. (Int. J. Radiat. Oncol. Biol. Phys. doi: 10.106/j.ijrobp.2009.11.060).

“This is the first time that MRI has been used to quantify proton-beam range errors,” researcher Michael Gensheimer from Vanderbilt told medicalphysicsweb. “The bone marrow acts as a radiation dosimeter. We used the fatty marrow conversion to see where the protons were going. We think that this is also the first time that MRI of bone marrow has been used for radiation dosimetry.”

Bone marrow responds to ionizing radiation in two phases. Initially, the injured tissue swells with blood and water. After a few weeks of radiation treatment, the blood-producing bone marrow begins to be replaced by fat, which is visible as a bright area on T1-weighted MR images.

Early changes in the bone marrow, seen just a few days after the start of treatment, could potentially enable adaptive treatment modification in future. “This would require the use of advanced MR sequences,” com-mented Gensheimer. “If one of these early scans showed significant errors in proton range, the treatment plan could potentially be modified for subsequent sessions.”

The relationship between radiation dose and the percentage of marrow converted to fat has not been previ-ously reported. The first step was to construct a curve relating radiation dose levels to the corresponding change in MR signal intensity.

To do this, the researchers aligned five patients’ post-treatment sacrum MR images to a CT image acquired in the treatment position. This enabled them to correlate the brightness of each spot in the MR image to a grid of planned radiation doses overlaid on

the CT image. By finding the averageMR signal intensity for each dose level, the team created a curve relat-ing the two quantities. Marrow signalintensity was found to increase even with low dose levels of a few Gy.

The group was then able to calcu-

late whether there was beam over- orunder-shoot in the distal dose fall-offregion in the lumbar spine. “We reg-istered 10 patients’ post-treatment sagittal lumbar spine MR images to their treatment planning CT,” explained Gensheimer.

He continued: “We divided each spine into small pieces. For each piece, we simulated range errors by shifting the planned dose distribu-tion in the direction of the beam. Foreach shift, we created a hypotheticaldose-signal intensity curve using the perturbed dose distribution and the MR signal intensity data. The beam over- or under-shoot that produced the dose-signal intensity curve closest to the true curve from the first part of the study was chosen as the most likely. This process was repeated for each piece of the spine,generating a map of range errors.”

This revealed that in a small per-centage of patients, there were largerproton range errors than expected, although the error did not exceed the uncertainty incorporated into the treatment planning margin. The team now hopes to apply the tech-nique to other tissues, such as the liver, which show MR changes in response to radiation.

Water calorimetry is a well recog-nised way of measuring the absorbed dose from proton therapy under ref-erence conditions, an important part of the calibration process. To date, this method of absolute dosimetry has only been applied to passively scattered proton beams. But passively scattered systems are expected to play a minor role in future proton therapy centres as the technology for deliv-ering scanned pulsed proton beams matures. So will water calorimetry work with scanned protons too?

The principle behind this method of calorimetry is that the absorbed dose induces a measurable tem-perature rise in water. This rise is measured in a sealed glass water ves-sel containing thermistor probes, which has been stabilized at 4 ºC. It is a relatively time-consuming tech-nique, but one that can work well in passively scattered proton beams if the equipment is set up correctly.

Up until now, calorimetry has not been used in scanned pulsed proton beams. This is because heat conduc-tion close to the beams’ characteristic sharp dose gradients could poten-tially lead to larger uncertainties in the measurements of temperature rise, and hence the absorbed dose.

Joakim Medin, medical physicist at Skåne University Hospital, Lund Uni-versity in Sweden, has now shown that water calorimetry is feasible in a high-energy scanned pulsed proton beam. The experimental work, car-ried out at the Svedberg Laboratory in Uppsala, suggests that this tech-nique should not necessarily be ruled out as a standard for dosimetry in future proton therapy systems (Phys. Med. Biol. 55 3287).

Medin made his water calorimetry measurements in a 180 MeV narrow scanned pulsed proton beam. The calorimeter was irradiated for 80 s after a fixed (120 s) delay and prior to a post-irradiation delay of 120 s. The 4 ºC water was replaced with water at room temperature and the measure-ments were repeated with two ioni-zation chambers.

Comparison of the calorim-etry and ionometry measurements allowed the beam quality correction factor (kQ) to be determined for the two ionization chambers. This value for kQ agreed well with that recorded in standard data tables and deviated slightly – but not significantly – from that determined from previous experimental measurements made in a passively scattered proton beam.

Theoretical calculations showed that the measurements were not compromised by heat conduction effects. But this may not be the case for pulsed proton beams with dif-ferent scanning patterns, Medin told medicalphysicsweb. “Sharp dose gradi-ents may still be a concern,” he said.

Future studies should assess the feasibility of water calorimetry at the centre of the spread-out Bragg peak, Medin added.

Calorimetry isOK for pulses

Spinal MR reveals proton beam range

Cell survival: the bio-phantom comprised two MicroWell plates, each containing 96 wells, mounted in a container filled with culture medium.

a) b)

c) d)

Thoracic spine: bright areas in thecentre of the MR image (as shownby the arrow) are regions where bone marrow has converted to fatin a scarring response to radiation.

GSI

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focus�on:�particle�therapy 7

In vivo verification of proton therapy allows monitoring of the some-times considerable uncertainties associated with treatment deliv-ery. Researchers at Massachusetts General Hospital (Boston, MA) have already demonstrated the fea-sibility of post-treatment “off-line” PET/CT scanning as a verification technique (Phys. Med. Biol. 54 4477). In a recent Red Journal publication, the team consolidates previous work by demonstrating which anatomical sites benefit most from this approach (Int. J. Radiat. Oncol. Biol. Phys. doi: 10.1016/j.ijrobp.2010.02.017).

PET/CT verification exploits the in situ creation of positron emit-ters along the path of the proton beam in the patient. PET provides a 3D map of the positron emitters, a representation of the positions reached by therapeutic protons. The measured activity distribution can be compared with a reference expected distribution, as provided by Monte Carlo simulations, allow-ing treatment efficacy to be moni-tored. Antje-Christin Knopf and co-workers performed this proc-ess for 23 patients with a range of tumour locations.

The team carried out PET/CT scans following proton therapy. It took between 11 and 24 min-utes for patients to walk from the department of radiation oncology to the department of radiology, and undergo set-up for their scan. This delay is an important factor in the accurate representation of pro-

ton range. In the interval between treatment and scanning, biologic “washout” – the removal of positron emitters by perfusion – occurs to varying degrees depending on the anatomical site. This distorts the activity distribution that would be seen were the patient to be scanned “online” directly after treatment, in the treatment room.

Key comparisonsThe investigators used GEANT4 and FLUKA Monte Carlo codes to gener-ate representations of expected pos-itron emitter activity distribution, the latter including semi-empiric modelling of washout. Where pos-sible, patients were positioned and immobilized for scanning in the same way as for their treatment. This aided co-registration of PET/CT images with planning CT images, in addition to minimizing patient motion, allowing more accurate comparisons with the co-registered Monte Carlo-predicted activity distributions.

Quantitative comparison of the simulated and measured activity distributions revealed a number of clinically pertinent findings. Accu-rate representation of abdomino-pelvic tumour sites using PET was challenging. The average absolute deviation between simulated and measured proton range was 5.2 mm versus 3.4 mm for intracranial sites, and 1.5 mm for cervical spine sites.

“The most perturbing factors for the range verification for the abdom-inopelvic tumours investigated in this study were biological washout effects and patient motion,” Knopf told medicalphysicsweb. “Besides

bringing the PET scanner closer to the radiation area, further techni-cal enhancements of the scanner itself, like the implementation of time-of-flight measurements, have potential. The reduction of the delay between irradiation and measure-ment, and the enhanced sensitivity of future PET scanners could per-mit shorter data-acquisition times. Thus the inf luence of biological washout effects and motion could be minimized.”

The researchers found the tech-nique better suited to cervical spine and intracranial tumour sites. Immobilization minimized patient motion effects. Furthermore, in the case of the former, the therapeutic protons range into relatively poorly perfused bony anatomy, limiting washout. Conversely, washout had a greater perturbing effect on intrac-ranial tumour sites, where protons range into well-perfused soft tissue.

Harald Paganetti, director of phys-ics research in radiation oncology, told medicalphysicsweb of plans for an in-treatment-room NeuroPET head scanner, developed in-house, which will minimize the uncertainty due to biologic washout in intracranial tumour sites. “So far, we have done a pilot study using the NeuroPET scanner with just two patients,” he said. “We have now applied for permission to use an additional 30 patients for another, more detailed study. In this following study, we want to study reproducibility, CT image registration and biological washout in particular.”

Jude Dineley is a medical physicist based in Sydney, Australia.

The ESTRO 29 meeting in Barce-lona, Spain, saw IBA introduce Lifebeam – a next-generation carbon-ion therapy system based on an advanced 400 MeV supercon-ducting isochronous cyclotron. The Belgian particle-therapy specialist started work on a specific accelerator for carbon-ion treatments a few years ago, with the aim of demonstrating that carbon ions can be accelerated with a cyclotron – as opposed to the synchrotrons used by other systems. The accelerator will be around 6 m in diameter, requiring a much smaller building to house the treatment sys-tem compared to the use of a syn-chrotron and, consequently, a lower cost carbon-ion treatment facility.

The emergence of a lower-cost carbon-ion therapy system could have a big impact in the particle therapy market. Currently, carbon-ion facilities cost up to twice that of a proton therapy facility – a fact that may well underlie the relatively low number of carbon facilities under construction or in operation.

The Lifebeam will offer both pro-ton and carbon-ion treatments. “Combining different particles in one accelerator requires good engi-neering and IBA is one of the few to invest in this,” explained IBA’s Claude Dupont. The accelerator will initially have a fixed beamline, though IBA is also working to develop a carbon therapy gantry system. “The chal-lenge there is that we don’t want to make it bigger than a proton therapy gantry,” he noted. In parallel with

the equipment development, a treat-ment planning system for carbon-ion therapy is also being created.

IBA recently announced the sale (subject to financing) of a prototype Lifebeam system to CYCLHAD – a joint venture between IBA, French company SAPHYN, and financial partners. IBA and SAPHYN will also be collaborating to further develop the potential of carbon-ion therapy – using the prototype for research into the radiobiology of carbon-ion beams.

IBA will be responsible for the installation of the prototype sys-tem in CYCLHAD’s research centre in Caen, France, along with a fixed-beam clinical research room and a fixed-beam physics research room. Dupont says that it will likely take around three years to create the building and prepare the equipment, and then two to four further years to demonstrate clinical performance.

As well as performing research, the new machine will also be used to treat patients with proton therapy in research mode. “The project will allow us to clarify the physics and radiobiology of carbon, while other projects will use the system to treat patients,” Dupont explained.

Details of the first experiment to show dose-dependent cell damage due to laser-accelerated protons have been published by researchers in Germany. The ultimate goal is to take this work through to clinical trials, a move that could eventually eliminate the need for synchrotrons or cyclotrons to administer proton therapy (New J. Phys. 12 085003).

“Huge technological progress was necessary to achieve this result,” said Ulrich Schramm, head of the Laser Particle Accelerator Division at Forschungszentr um Dresden- Rossendorf (FZD). “The major improvement was in the laser accel-erator system followed by the dosi-metric monitoring development. It was absolutely crucial to bring both of these pieces of technology together simultaneously – their co-existence was vital.”

The key enabling factor in this work was generating ultrafast laser pulses with significantly high peak power, as this dictates the energy of the protons. Recent advances have resulted in laser sources emitting pulses with peak powers of around 100 TW at a repetition rate of several

shots per minute. Such sources are capable of generating protons with energies up to 20 MeV.

“The proton beam is generated under vacuum conditions. In order to study living cells, we need to bring the proton beam from vacuum to air and perform the experiment over a

short time span,” commented Joerg Pawelke, head of the OncoOptics research group at OncoRay, the Centre for Radiation Research in Oncology at TU Dresden. “Our laser operates in a true ‘shot-on-demand’ mode and in combination with our dosimetric system we can apply a

prescribed dose to the cells.”Ultrafast pulses from the team’s

Ti:sapphire laser are brought to a focus on a 2 µm-thick Ti foil, where peak intensities reach 1021 W cm–2. Protons are emitted from the foil with a range of energies up to 20 MeV and are filtered before entering an integrated dosimetry and cell irra-diation system (iDocis) some 20 cm downstream from the target foil. The iDocis module comprises an ioniza-tion chamber made from ultrathin foils for online dosimetry and a Fara-day cup inset for absolute dosimetry, which can be replaced by a cell holder inset for cell irradiation studies.

Schramm, Pawelke and colleagues irradiated three squamous cell carci-noma with 12, 20 and 29 laser-accel-erated proton pulses delivering a dose of 1.5, 2.7 and 4.1 Gy, respectively. An increase in the number of DNA dou-ble-strand breaks was observed as the dose increased, indicating dose-dependent damage to the cells.

The team is now performing fur-ther cellular studies to determine dose-effect curves for several cell lines and yield the biological effec-tiveness of laser-accelerated proton

beams. The longer-term aim is to move on to animal and eventually clinical trials. However, in order to make this happen, further improve-ments will need to be made to both the laser system and the dosimetry monitor.

“With the 20 MeV that we have cur-rently, the beam penetration depth in water is on the order of a few mil-limetres which is sufficient for cell irradiation,” explained Pawelke. “The required proton energy depends on both the tumour size and its depth. For animal irradiation with a tumour size of a few millimetres, even close to the skin’s surface, we will need proton energies of 30 MeV or higher. For patient irradiation with a tumour size of centimetres, we will need even higher energies of up to roughly 220 MeV. In turn, this will require the peak power of the laser to increase by an order of magnitude.”

The team’s dosimetry system will also have to be upgraded. “We are using a cell monolayer in our current experiments, which is flat,” Pawelke told medicalphysicsweb. “For patients, we will require an accurate three-dimensional monitor.”

PET verification: where is best?

IBA’s compact carbon therapy

Progress in laser-accelerated protons

Cell irradiation: co-author Doreen Naumburger sets up the experiment at the FZD’s high-power laser Draco (Dresden laser acceleration source).

On Show: IBA highlights Lifebeam at the ESTRO technical exhibition.

focus on: nanomedicine8

Nanoparticles: detect, image, treatNanotechnology is increasingly being applied to medical imaging and therapy. Here, we take a look at some recent developments.

l Scientists at the University of Bath in the UK are exploiting nan-otechnology to create an advanced wound dressing that can detect and treat infection. When triggered by the presence of pathogenic bacteria in the wound, the dressing releases antibiotics from nanocapsules. It also changes colour when the antibiotic is released ( J. Am. Chem. Soc. 132 6566).

“The dressing is only triggered by disease-causing bacteria, which pro-duce toxins that break open capsules containing the antibiotics and dye,” explained University of Bath project leader Toby Jenkins. “This means that antibiotics are only released when needed, which reduces the risk of the evolution of new antibiotic-resistant super-bugs such as MRSA.”

The researchers have already tested fabric coated with the nano-capsules, which have been shown to react specifically to harmful bacteria. Over the next four years the project team – 11 partners across Europe and Australia – will work to integrate the technology into a suitable dressing and examine cost-effective produc-tion routes.

l A combination of laser-activated nanoparticles and adult stem cells appears to destroy atherosclerotic plaque and rejuvenate the arteries, according to a study reported at the recent American Heart Association conference: Basic Cardiovascular Sciences 2010 Scientific Sessions. The study treated 19 pigs with silica-gold nanoshells, while 18 control animals received saline solution. Nanoparticles were delivered with or without stem cells.

After the nanoparticles were heated by exposure to laser light, they burned away arterial plaque. Plaque volume decreased by 28.9% (average across the three groups) immediately after the procedure and by 56.8% six months later. In the con-trol group, plaque volume increased

by an average of 4.3%. The greatest reductions occurred in treatment groups that received stem cells along with the nanoparticles. These groups also showed signs of new blood ves-sel growth and restoration of artery function.

“This unique approach holds promise for use in humans for acute care and urgent restoration of blood f low,” said lead author Alexandr Kharlamov, from the Ural State Med-ical Academy in Russia. “Nanoburn-ing in combination with stem cell treatment promises demolition of plaque and functional restoration of the vessel wall.” l A novel nanoparticle-based imag-ing technique from the University of Washington (Seattle, WA) claims to provide a first step towards detecting single cancerous cells. While nano-particles are promising contrast agents for ultrasensitive imaging, in all techniques that do not use radio-active tracers, their weak signals tend to be overwhelmed by signal from surrounding tissues. To combat this, the researchers have developed a multifunctional nanoparticle that eliminates this background noise (Nature Comms. 1 41).

The 30 nm particle comprises an iron oxide magnetic core with a thin gold shell that surrounds but does

not touch the centre. The gold shell absorbs infrared light, enabling its use in photoacoustic imaging. The researchers applied a pulsing mag-netic field at a specific frequency, which shakes the nanoparticles by their magnetic cores. They then recorded a photoacoustic image and used image processing techniques to remove everything except the vibrat-ing pixels.

Experiments with synthetic tis-sue showed that this technique can almost completely suppress a strong background signal. Future work will try to duplicate the results in lab ani-mals. “Today, we can use biomarkers to see where there’s a large collection of diseased cells,” said co-author Matthew O’Donnell. “This new technique could get you down to a very precise level, potentially of a single cell.”

l Particles of iron oxide could pro-vide simultaneous imaging and treatment of the brain tumour glioblastoma multiforme, report researchers at Emory University School of Medicine (Atlanta, GA). The Emory team conjugated 10 nm-diameter iron oxide particles to antibodies that selectively bind to a molecule on the surface of gliob-lastoma cells. After treatment with these nanoparticles, a significant decrease in glioblastoma cell sur-vival was observed, while no toxic-ity was observed for normal human astrocytes (Cancer Res. 70 6303).

The researchers used convection-enhanced delivery – continuous infu-sion of fluid under positive pressure – to introduce the antibody-linked nanoparticles into mice implanted with human glioblastoma cells. The particles lengthened the median survival of the mice to 19 days, com-pared with 16 days for bare particles and 11 days for no particles. The par-ticles also made the tumour visible via MRI, darkening the area of the brain where the tumour was located.

The team now plans to translate the use of bioconjugated iron-oxide nanoparticles for use in canine brain tumour models and into a human clinical trial for patients suffering from brain cancer.

Toby Jenkins: coating prototype dressings with the nanocapsules.

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9focus on: nuclear medicine

SPECT-based planning: methods matterUp to 20% of lung-cancer patients treated with radiotherapy go on to develop radiation-induced lung inju-ries. While it’s possible to estimate the risk of such symptoms occur-ring, current methods are far from ideal as they assume homogenous lung function. What’s needed is a way to determine the distribution of function throughout a patient’s lung and incorporate this information into the radiotherapy plan.

SPECT lung perfusion scans can provide such functional informa-tion. SPECT-based parameters can, however, be sensitive to the image reconstruction method used.

A study headed up at the Univer-sity of British Columbia (Vancouver, BC) and Vancouver Cancer Centre has evaluated the impact of differ-ent SPECT image reconstruction algorithms on SPECT-guided radio-therapy planning. The researchers examined approaches based on func-tional lung segmentation and SPECT-weighted mean dose (SWMD) (Int. J. Radiation Oncology Biol. Phys. doi: 10.1016/j.ijrobp.2009.11.035).

“In most clinics, the SPECT recon-struction algorithm is a ‘black box’ that comes with the vendor’s soft-ware,” explained lead author Lingshu Yin. “Not much attention is paid to the reconstruction; specifi cally, the attenuation correction is often not

applied. Scatter correction is even more problematic as a wide range of different methods exists.”

The Canadian team examined nine patients with lung cancer. Each patient underwent a SPECT scan, then four SPECT image sets were generated, using four different image reconstruction methods. The ven-dor’s software, as employed clini-cally, served as a reference method. This included resolution recovery and attenuation correction, but does not account for scattered photons.

The next two reconstruction methods included resolution recov-ery and attenuation correction, and also incorporated scatter cor-rection, either using a broad-beam attenuation map (method two) or an advanced approach that models scat-ter distribution using patient specifi c

attenuation maps (method three). The fourth method only included resolution recovery correction.

Yin and colleagues examined the impact of the reconstruction method on functional lung segmen-tation. For each patient, the lung was segmented by applying a threshold (between 10 and 90% of maximum SPECT intensity) and defining the functional volume as all voxels above that threshold. For each threshold level, the researchers calculated the agreement between images recon-structed using the vendor’s software and each of the three other methods.

Compared with reference images, reconstructions that included atten-uation and scatter correction (meth-ods two and three) provided lower volumes of functional lung for most patients – attributed to more accu-

rate scatter correction removing image blur from scattered photons. With a clinically relevant thresh-old of 40–60% , the differences in segmented functional volume were around 25%. SPECT reconstructions performed with resolution recovery correction only (method four) over-estimated functional lung volume considerably at this threshold, and by more than 100% in some cases.

To study the effect of SPECT recon-struction on SWMD, the research-ers tested the four reconstruction methods at a variety of fi eld sizes. The largest differences were found when comparing reference SPECT images to those reconstructed using method four. The average difference between the techniques was 7.12%, with a maximum difference of 27%.

For reconstruction methods that included attenuation correction, the variation was smaller. Here, the over-all mean differences were 1.63 and 1.74%, with maximum differences of 7.53 and 12.5%, for methods two and three, respectively.

The researchers concluded that lung function information from SPECT studies is indeed dependent on the reconstruction algorithm. Yin suggests that the SWMD approach is preferable, particularly to ensure consistency within inter-site clinical trials of SPECT-guided radiotherapy.

Imaging gauges therapy successA series of studies published in the Journal of Nuclear Medicine demon-strate how molecular imaging plays a critical role in planning and evalu-ating cancer treatments. At Memo-rial Sloan-Kettering Cancer Center, researchers performed planar imag-ing and SPECT/CT on patients with thyroid cancer. SPECT/CT provided information that reduced the need for additional cross-sectional imaging in 29 patients and redefi ned initial risk recurrence estimates in seven of 109 patients ( J. Nucl. Med. 51 1361).

I n v e s t i g a to r s a t L u d w i g -Maximilians-University, Germany, used PET/CT with 68Ga-DOTATATE to monitor patients with neuroendo-crine tumours undergoing peptide receptor radionuclide treatment. The study, which evaluated 33 patients, suggests that PET/CT may contribute to the early prediction of treatment outcome in such patients ( J. Nucl. Med. 51 1349). Researchers at the Netherlands Cancer Institute evaluated the use of PET for assessing treatment response in patients with non-small cell lung cancer. In a study of 23 patients treated with a molecu-lar-targeted agent, FDG PET/CT was used to monitor disease before and one week after drug administration. Results suggest that FDG-PET/CT can predict response early in the ther-apy course ( J. Nucl. Med. 51 1344).

Key contours: functional volumes defi ned using four different SPECT reconstructions. AC = attenuation correction, SC = scatter correction.

AC SC

Method 1 yes no

Method 2 yes approximation

Method 3 yes direct modelling

Method 4 yes no

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Magnetic induction tomography (MIT) is a non-contact method for mapping the electromagnetic prop-erties of tissue. It works by measur-ing perturbations caused by objects within an applied magnetic field and, as magnetic fields easily penetrate the skull, could prove suitable for imag-ing conductivity changes within the brain. As such, MIT is under investi-gation for detection of brain lesions such as cerebral haemorrhage.

When diagnosing stroke in a clini-cal setting, it is unlikely that pre-stroke data will have been recorded. But by obtaining measurements at two frequencies (frequency- difference MIT), an image of conduc-tivity differences between the two data sets can be constructed. Because different tissue types have distinct frequency-dependent conductivi-ties, the lesion could be distinguish-able from surrounding tissues.

At Swansea University in the UK, a team of engineers and medical physi-cists from the Schools of Engineer-ing and Medicine have performed a series of studies modelling the ability of frequency-difference MIT to image cerebral haemorrhage. In their latest publication, Massoud Zolgharni and colleagues investi-gate the feasibility of detecting stroke with a hemispherical MIT coil array (Physiol. Meas. 31 S111).

“Hemispherical arrays conform better to the brain and therefore offer an improved imaging sensitivity to the region of interest,” explained Zolgharni. “Furthermore, by using such an array, a larger number of the exciter/sensor coils can potentially be employed, enabling acquisition of more MIT data.”

The Swansea team simulated MIT measurements of haemorrhagic stroke, using an anatomically real-istic head model comprising 12 tis-sue types. The researchers initially simulated three types of coil array: a conventional annular array with 16 pairs of exciter/sensor coils; a hel-met array, comprising 28 exciter and 28 sensor coils positioned on a hem-isphere with radius 100 mm; and a helmet array with radius 120 mm.

The team first examined a simu-lated large peripheral stroke (49.4 ml in volume), reconstructing images of the conductivity changes between 1 and 10 MHz. While all three coil configurations could visualize this large stroke, the 100 mm hemispher-ical array performed the best and was used for the remainder of the study.

Next, random noise was added to the simulated data to evaluate its effect on the reconstructed images. With 1 m° (millidegree) of added phase noise, the stroke was still well visualized on the images, while add-ing 17 m° led to a noise-dominated image. A phase noise level of about 3 m° appeared to be acceptable when imaging this particular lesion, which resulted in an error of about 19% in the reconstructed images.

The researchers also examined the effects of systematic errors such as size-scaling errors or shifts of the head within the helmet. Frequency-difference images reconstructed from data modelled with such errors revealed artefacts near the periphery of the images.

The artefacts were quantified by evaluating the image error using the same acceptance criterion employed for random noise (error ≤19%). The researchers concluded that a dis-placement error of no more than 3–4 mm, and a scaling error of below 3–4%, should not cause unaccept-ably large artefacts on the images.

Finally, the team simulated a smaller peripheral stroke (volume 8.2 ml), and a small deep stroke (7.7 ml). Limited spatial resolution resulted in poor visualization of the small peripheral stroke, while the deep stroke could not be seen at all, due to artefacts present on the image of the normal head.

“Improving the image reconstruc-tion algorithms, as well as adapting the MIT hardware to reduce the phase noise in the measured sig-nals, could help enhance the imag-ing of smaller strokes,” suggests Zolgharni. “Another possibility could be to use more than two fre-quencies to define the ‘frequency signature’ of the stroke.”

MIT maps the brain

Columns, left to right: true conductivity rise; reconstructed conductivity rise for annular array, 100 and 120 mm helmet arrays; images from the 100 mm helmet array when the head was modelled without the stroke.

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The true synergy of optical and radio-logical imaging will only be achieved when the two techniques provide data or diagnoses that could not be obtained using either approach alone. That’s the conclusion of Brian Pogue and colleagues at Dartmouth Medical School (Lebanon, NH) in their recent review article discuss-ing the fundamental limitations and advantages of combined radiologic and optical imaging systems (AJR 195 321).

Although combined imaging sys-tems are now very much in evidence at the preclinical stage, the optimal way to integrate the techniques and exploit the results is still unclear. Those issues aside, the benefits of having a hybrid system for clinical applications are sufficient to inspire a significant research effort into reach-ing this goal.

“The advantage of a combined system comes in the marriage of structural imaging with tissue func-tional imaging,” Pogue, professor of engineering sciences in the Thayer School of Engineering at Dart-mouth College (Hanover, NH), told medicalphysicsweb. “A combined sys-tem can be used to study things such as rapid blood flow changes while still having X-ray images. Alternatively, metabolic function of the mitochon-dria in a tissue can be followed, while still imaging where the signal is com-ing from with X-rays.”

The most significant differences between radiologic and optical imag-ing occur when you look at the reso-

lution that can be achieved and each technique’s sensitivity to contrast agents. Radiological imaging is ideal for analysing hard tissues and has high spatial resolution but is mostly used to resolve just one contrast agent at a time. In comparison, opti-cal imaging has relatively low resolu-tion – because of the high scattering of light in tissue – but has the poten-tial to image up to 10 contrast agents simultaneously.

“Good detectors can compen-sate for the strong attenuation of light in tissue, but only in transmis-sion mode,” commented Pogue. “In reflectance or remittance mode, the light from the surface is orders of magnitude larger than the light from deeper structures, and so it is impos-sible to gain signals from deeper than a few centimetres. The geometry of the light input and output is often one of the largest limitations for opti-cal imaging, and then combining this with X-ray detectors just makes the systems bulky. However, there are good examples of interfaces that work in the pre-clinical world, such as

those by Caliper LifeSciences, VisEn Medical and Carestream Health.”

According to Pogue, integration will likely require specific systems designed for particular organs or applications. A good example of this is the systems already developed for breast cancer where optical imaging is used after X-ray mammography.

“Instruments for intra-surgical X-ray or fluoroscopy combined with optical fluorescence will likely be the next major development in this path-way, as surgeons require as much information as they can get quickly to make decisions about procedure and excision,” explained Pogue. “I expect surgical systems integrated with interventional imaging tools such as fluoroscopy or scintigraphy will be successful first.” This could require the use of semi-automated segmenta-tion of the radiological image, espe-cially when following response to therapy over time.

“In neurosurgery, the pre-operative radiological image is already being used in concert with the fluorescence image during surgery,” said Pogue. “This will likely become more uti-lized in places such as breast cancer surgery guidance. The use of optical imaging together with pre-operative or interventional imaging tools is commonly done, but mostly still for surface imaging. The key transition will come when better molecular tracers become available. This will happen, but it may take a few years for them to work their way through to multicentre clinical trials.”

Jacqueline Hewett is a freelance science and technology journalist based in Bristol, UK.

Hybrid imaging: a tumour in this rat cranium not seen in the MicroCT image is visualized by fluorescence tomography (overlaid in red/yellow).

X-ray and optics: imaging synergy

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